Aristolochic acid (AA) is a potent human nephrotoxin and carcinogen that plays a key role in the pathogenesis of renal fibrosis and UC, often found in traditional Chinese medicine for digestion and weight loss. It’s also used in ESRD patients to reduce serum creatinine (30). AA exposure may explain the higher rates of UC post-transplant in the Chinese population (25, 31), especially among KTRs with a history of Aristolochic Acid Nephropathy (AAN), who face a greater risk of primary kidney UTUC (32). Traditional Chinese medicines with AA, like Isotrema manshuriense (Kom.) H. Huber, may raise UC risk in KTRs. KTRs should be cautious about herbal ingredients’ impact on kidney function and cancer risk, particularly those with AA. In addition, Rhubarb extracts are also key components in certain traditional formulations, like uremic clearance granules. It is mainly used for renal dysfunction or chronic kidney disease, and may also cause UC post KT. Thus, overlooking other Chinese herbal products is unwise, as they too can have serious effects (23, 33), as shown in Table 1. In western countries, the etiological factor of Chinese herbal medicine intake is rarely mentioned. Instead, the common etiological factors for UC after renal transplantation in these countries are more closely associated with the use of immunosuppressants, abuse of analgesics, and other related factors. The impact of Chinese herbal medicine intake on the development of this cancer is far less significant than that in China (23).

Evidence indicates that immunosuppressive therapy significantly raises cancer risk in KTRs (34). While these agents prevent kidney rejection, they also impair immune surveillance, allowing tumor cells to evade detectionand and clearance by the immune system, thus increasing UC risk (35). Additionally, long-term use of calcineurin inhibitors (CNIs) like cyclosporine and tacrolimus, as well as mammalian target of rapamycin (mTOR) inhibitors can directly damage DNA, further elevating UC risk (36). However, the lack of immunosuppressants, particularly sirolimus, is also linked to UC post KT. Lai HY et al. found early UTUC post KT was associated with not using sirolimus, which correlated with improved disease-free survival (DFS). And high levels of 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) in matched normal tissues suggest AA exposure and could be a predictive and prognostic biomarker for new UTUC cases post KT (37). In addition, donor transmission, like a deceased transplant kidney with hidden microtumors, can lead to cancer growth after immunosuppressive therapy (38). Thus, it’s crucial to balance anti-rejection and anti-cancer treatments.

KTRs face a higher risk of viral infections due to immunosuppressive therapy, which may contribute to UC development (39). Human polyomavirus (HPyV), a non-enveloped double-stranded DNA virus, can integrate into the host genome, causing cell cycle disruptions and gene mutations, thereby increasing UC risk (34). BK polyomavirus (BKPV), a common HPyV, usually remains latent in healthy individuals but can reactivate and replicate in KTRs due to prolonged immunosuppressive treatment (40, 41). BKPV’s carcinogenic mechanism may involve its encoded Large T Antigen (LTAg), which can bind to and inactivate the host’s tumor suppressor genes p53 and pRB, resulting in unchecked cell cycle progression and tumor development (42). Chu YH et al. discovered that TAg-positive UC exhibited BKPV integration and higher levels of p16 and p53 compared to TAg-negative UC. Additionally, TAg-positive UC was more likely to present at advanced stages (50% T3-T4), associated with lymph node metastasis (50%), and had a higher UC-specific mortality rate (50%) (43). Kenan DJ et al. discovered that in KTRs with high-grade UC, BKPV disrupts VP1 protein expression and viral replication, meanwhile, deletions occur in the non-coding control region (NCCR). They suggest BKPV contributes to UC by disrupting cell cycle regulation and enhancing genetic instability (44). According to Yan L et al., all instances of polyomavirus-positive UC appeared more than 9 years following transplantation, indicating that the ‘time lapse’ could significantly influence polyomavirus-associated UC and calls for continuous observation (7). Jin Y et al. studied BKPyV integration in the bladder cancer of KTRs using whole-genome and viral capture sequencing. They identified a unique multi-site, multi-fragment linear integration pattern, unlike earlier models, possibly involving microhomology end joining (MMEJ) and nonhomologous end joining (NHEJ). The number of integration sites might correlate with tumor invasiveness, suggesting that monitoring viral load could help prevent related cancers (45). Figure 2 illustrates the BKPV’s mechanism of action. Besides, John cunningham virus (JCV) is believed to be linked to UC. While its carcinogenic role in the general population isn’t fully established, case reports in KTRs suggest JCV’s involvement in UC, as JCV DNA is frequently found in tumor tissues and is closely associated with tumor development (46). It should be noted that much of the current evidence on the roles of BKPV and JCV in carcinogenesis is primarily drawn from studies of bladder cancer rather than urothelial carcinoma more broadly.

ESRD patients’ urine contains toxins that can lead to UC (47). Most ESRD patients, whether or not they have had a kidney transplant, experience decreased urine output, leading to prolonged retention of metabolic toxins such as aromatic amines and polycyclic aromatic hydrocarbons, and inflammatory mediators in the bladder mucosa. This persistent exposure induces chronic oxidative stress and DNA damage in urothelial cells, creating a pro-carcinogenic microenvironment. Additionally, anuria reduces the elimination of potential carcinogens, such as aristolochic acid metabolites and viral particles that may accumulate in the bladder tissue over time. The bladder, positioned downstream in the urinary tract, has a larger surface area than the upper tract. KT could increase urine flow flushes the bladder. Ho CJ et al. propose this might partly account for the higher UC incidence in KTRs, with UTUC being more common than UBUC (19). Hydronephrosis is also linked to UC development due to urine stasis, recurrent UTI, chronic inflammation of the urinary tract lining, and toxin buildup, resulting in a toxic local environment. Ho CJ et al.’s study confirmed that native kidney hydronephrosis is a remarkably strong independent predictor for post-KT UTUC, with an Odds Ratio (OR) of 35.32 (95% CI, 17.99–69.36; p < 0.001) (19). Among 67 KTRs with UTUC, the incidence of hydronephrosis was 68.7%, significantly higher than the 4.8% in those without UTUC (19). Ho, C.J. et al. discovered that patients with new-onset hydronephrosis post KT had a higher likelihood of developing UC, particularly UBUC. Notably, synchronous UTUC was observed significantly more often in the NKH group (65.2% vs. 21.1%; p = 0.004), which reflects the highly aggressive and multifocal pan-urothelial field change in this patient population. This synergy further underscores the clinical significance of NKH as a key radiological marker for UC screening (48). Thus, diligent monitoring and prompt intervention are crucial for these patients.

UC is also associated with smoking. In the general population, smoking is one of the primary risk factors for bladder cancer, with approximately 50% of bladder cancer cases linked to smoking (49). Harmful substances from smoking, like aromatic amines and polycyclic aromatic hydrocarbons, enter the bloodstream, reach the bladder, and can cause DNA mutations, leading to cancer. In KTRs, smoking significantly affects bladder cancer risk. Liu S et al. found smoking to be an independent risk factor for bladder cancer post KT. Their analysis showed that smoking raises bladder cancer risk 6.1 times in patients with polyomavirus, while polyomavirus replication in smokers increases the risk 9.7 times, indicating a potential synergistic effect (50).

Besides, risk factors such as exposure to arsenic fumes, analgesic abuse, and chronic inflammatory status in KTRs contribute to the predominance of UTUC among female patients (51–53). Uremia per se have been reported to be predisposing factors for invasive bladder cancer in RTRs (54). Studies have indicated that using anthranoids and chemical laxatives for a year is significantly linked to UTUC risk in RTRs (55). An Egyptian report found that 0.4% of 1865 kidney transplant patients had bladder cancer, often linked to prior schistosomiasis infection (56). Genitourinary system diseases, such as reflux or obstructive uropathy, as well as congenital anomalies (accounting for approximately 40%), are also closely related to the occurrence of UC in RTRs (57).

Ultrasound is a convenient and reproducible method for detecting kidney and ureter abnormalities, including hydronephrosis and ureteral masses, and is useful for initial UC screening in KTRs (58). Notably, given that Native Kidney Hydronephrosis (NKH) has been validated as an extremely strong independent predictor of post-KT UTUC (19), ultrasound is not only suitable for initial UC screening but also serves as the most effective non-invasive, high-yield method for periodic NKH monitoring in KTRs. This allows for timely identification of NKH, a key radiological marker that signals an elevated risk of UC development. Computed Tomography (CT) offers a clear view of a tumor’s location, size, shape, and relation to nearby tissues, aiding in staging and treatment planning, especially for KTRs suspected of UC. They can confirm lymph node metastasis (59). Retrograde pyelography can detect filling defects in the renal pelvis and ureter, useful for diagnosing UTUC. Each imaging method has its pros and cons, so combining multiple techniques is common in clinical practice to enhance diagnostic accuracy.

Cystoscopy is essential for diagnosing bladder cancer by allowing direct bladder lesion visualization and tissue sampling for biopsy. Ureteroscopy with biopsy is used for diagnosing tumors in the renal pelvis and ureter. RTRs with AAN history should have regular cystoscopies (60). However, atrophy and upper urinary tract strictures complicate UTUC diagnosis, often making lesion access and biopsy difficult.

Urinalysis can identify hematuria, but its occurrence is much lower in the KT group compared to the non-KT group. Relying solely on hematuria for screening may delay diagnosis, so it is recommended to combine it with imaging methods like ultrasound and CT for early detection of UTUC post KT (16). Although urinalysis can detect cancer cells, its sensitivity is low, especially due to reduced urine volume from ESRD, which limits detection mainly to bladder lesions. The presence of decoy cells and highly atypical cells in urine suggests potential malignancy, warranting further confirmation through immunohistochemistry, such as SV40. Odetola, O.E., et al. found that 17 of 36 cases had urine cytology tests, with 11 positive results and 5 showing both decoy and malignant cells (61). The effectiveness of urine cytology for detecting UTUC is debated (19), but washed urine cytology is crucial in standard UTUC examinations. Bilateral upper tract washing cytology is particularly useful for excluding high-grade UTUC in patients with repeated uncertain urine cytology and negative cystoscopy results (62).

Advanced, multifocal, or bilateral UTUC lesions have a poor prognosis, with radical nephroureterectomy (RNU) and excision of cuff of bladder as standard treatments in KTRs (63). Both open nephroureterectomy and laparoscopic nephroureterectomy (LNUT) have similar operative times, but the laparoscopic approach results in less blood loss, shorter hospital stays, and better oncological outcomes (64). However, the use of LNUT in KTRs with UTUC is limited, and there is no consensus on whether open or laparoscopic surgery should be used for patients with UTUC post KT. Wu JT et al. performed LNUT on 11 patients with in situ UTUC post KT, reporting no intraoperative complications, an average hospital stay of 6.7 days, stable renal function, and minimal disease progression. They concluded that LNUT is safe and effective, offering benefits like minimal trauma, quick recovery, and acceptable oncological outcomes. LNUT can be executed through either a retroperitoneal or transperitoneal method. The retroperitoneal laparoscopic technique efficiently reveals the renal pedicle, necessitating less dissection and minimizing the risk of injury to intraperitoneal organs. The primary drawback of this method is the restricted working area due to the heightened risk of harming the nearby transplanted kidney (65). Wu JT et al. noted that the laparoscopic method offers great access to the kidney and renal hilum and can be easily switched to open distal ureterectomy to protect the transplanted kidney from damage due to severe adhesions from distal ureteral cancer. They also routinely use this approach for lymph node removal (66). While LNUT offers several benefits, its use in treating UTUC in KTRs is challenging, particularly when the primary tumor and transplanted kidney are on the same side, as limited space heightens the risk of damaging the transplant (65, 66). Chang NW et al. note that despite the challenges of open surgery for KTRs, including scar tissue around the graft, and difficult ureteral dissection in laparoscopic procedures, in their team, the proportion of open surgery was higher in the KT group than in the non-KT group (67). Despite limited randomized trials, numerous case reports suggest that transplant recipients gain from laparoscopic surgery, experiencing less pain, shorter hospital stays, quicker recovery, and fewer wound complications (68). The key concern is the long-term outcomes of LNUT for these patients, but studies are scarce. Long-term follow-up is essential to evaluate LNUT’s effectiveness in treating UTUC in KTRs.

There is ongoing debate about performing prophylactic contralateral RNU for KTRs with unilateral UTUC, as studies indicate KTRs have a high risk of developing synchronous bilateral UC (17, 51). Furthermore, recurrence on the opposite side after a unilateral radical nephroureterectomy (URNU) is common. According to Fang et al, patients who underwent transplantation had a more than 15 times higher risk of developing tumors on the opposite side compared to those who did not undergo transplantation, with 60% of post-renal transplant patients developing contralateral tumors (69). The study by Huang et al. found that among patients who had renal transplants or were on regular dialysis, the contralateral recurrence rate over five years was 38.3%, with every recurrence occurring within the first three years (70). Therefor, they recommend simultaneous bilateral radical nephroureterectomy (SBRNU) once one side is diagnosed (69, 70). Zhang Q et al. studied the effectiveness of SBRNU versus URNU in treating newly diagnosed UTUC post KT, involving 48 patients (21 SBRNU, 27 URNU). SBRNU resulted in longer surgeries and hospital stays, but similar blood loss and perioperative complications compared to URNU. At a 65-month follow-up, SBRNU showed better progression free survival (PFS) and cancer specific survival (CSS). The author suggests that SBRNU can enhance survival rates without impacting perioperative outcomes. It may be a suitable treatment for high-risk patients, particularly females with prolonged AA exposure, prone to bilateral UTUC post KT (71). Lin KJ et al. studied 44 cases of KTRs with UTUC, finding that PFS was significantly better in the SBRNU group than in the URNU group (72). Kao YL et al. observed that 41% of UTUC cases post KT were synchronous and recommended prophylactic SBRNU due to high contralateral recurrence rates and lack of early screening methods. However, given the 0.2%–2.63% incidence of UTUC post KT, they advised against routine prophylactic SBRNU for all patients, suggesting instead close postoperative monitoring. SBRNU with bladder cuff resection is strongly recommended if UTUC is suspected or if there is high risk, while considering patient preferences (51). While this method reduces the risk of postoperative urinary tract infections and upper urinary tract tumor recurrence, it may raise the risk of other complications due to reduced residual urinary tract (56). Lang, H et al. performed systemic SBRNU on four patients but did not find any tumors (73). Therefore, some authors suggest that SBRNU heightens health risks for KTRs, recommending URNU first, with subsequent careful monitoring and evaluation (66). In summary, treatment for KTRs with unilateral UTUC should be personalized. The benefits of prophylactic SBRNU are uncertain, so it shouldn’t be standard practice. It’s important to weigh the risk of postoperative infections or tumor recurrence in the upper urinary tract against the advantages of maintaining some urinary function. For patients with AAN at high risk of synchronous UTUC, decisions should be made after thoroughly evaluating renal function, tumor traits, and surgical tolerance.

Muscle invasive bladder cancer (MIBC) occurs in 37% of KTRs, a higher rate than in the general population, with most cases diagnosed at advanced stages (74, 75). Treating bladder cancer in KTRs is complex due to the need to balance effective cancer treatment with maintaining kidney function and proper urinary drainage. Due to the aggressive nature of UC in KTRs, a conservative endoscopic approach should not be applied to the KT population. While transurethral resection of bladder tumor (TURBT) appears reasonably safe for low-risk diseases in the general population (76). MIBC is generally more aggressive than non-muscle invasive bladder cancer (NMIBC), with a higher progression rate, poorer prognosis, and lower survival rate (77). Therefore, early radical cystectomy (RC) and pelvic lymph node dissection (PLND) are widely recommended (78). Comparative data from a series of cystectomies indicate that extended lymph node dissection improves overall survival (79), though some researchers prefer to avoid it on the transplant side to prevent blood supply damage. If needed, the opposite side’s dissection can be extended (77). When a cystectomy is needed in patients who have undergone a kidney transplant, the choice of urinary diversion must be evaluated and adjusted according to the renal transplant’s performance. Reconstruction options vary from basic cutaneous ureterostomy to an orthotopic neobladder, with the latter advised only for patients whose glomerular filtration rate is stable at 50 ml or higher. In the past, ileal conduits or Kock pouches were used for renal transplant recipients needing cystectomy, despite the high risk of renal infection and graft deterioration in immunosuppressed patients (77). Additionally, urinary diversion during cystectomy is crucial, with the studer in situ bladder procedure being a popular choice after RC. This technique uses an ileum segment to create a urinary reservoir, connecting the ureter to the urethra, allowing patients to regain near-normal urinary function. It’s suitable for those with MIBC or high-risk NMIBC, requiring careful evaluation of intestinal function and urethral sphincter status. Successful cases include KTRs undergoing this procedure. Manassero F et al. assert that the studer technique is effective for urinary tract reconstruction in bladder cancer patients post KT due to its adaptability to short ureters and its ability to prevent reflux (77, 80). However, when selecting a urinary diversion method, consider patient comfort and complication risks. While orthotopic neobladder is more physiologically suitable, it can heighten urinary tract infection risk from intermittent catheterization and cause metabolic issues due to urine absorption by the intestines. Yavuzsan AH et al. conducted a RC with ileal conduit diversion on a young female with invasive bladder cancer, featuring sarcomatoid and squamous cell variants, three years post KT. The procedure was likely chosen for its simplicity and lower complication risk, crucial for preserving the transplanted kidney and the patient’s overall health (81). In complex cases with both upper and lower urinary tract lesions, advanced surgeries like laparoscopic bilateral nephroureterectomy with PLND and orthotopic neobladder may be necessary (82).

UC is often multifocal, and adjuvant chemotherapy is crucial for advanced or high-risk cases. Adjuvant chemotherapy plays a significant role in the comprehensive treatment of UC post KT. However, immunosuppressed patients may poorly tolerate chemotherapy and face more complications, requiring careful patient selection. While platinum-based chemotherapy is the primary treatment for advanced UC, its nephrotoxicity limits its use in KTRs (83). Chang NW et al. analyzed 57 patients with advanced UTUC (stage T2 or higher) who underwent nephroureterectomy and bladder cuff excision, followed by adjuvant chemotherapy with gemcitabine plus cisplatin or carboplatin. The study included 23 KTRs and 34 non-transplant patients. Results indicated the five-year disease-free survival (DFS) and overall survival (OS) rates were 45.7% vs. 70.2% and 62.8% vs. 77.6%, for the KT and non-KT groups. Hematologic toxicities showed significant differences between the KT and non-KT group. The KT group had more severe neutropenia, anemia, and thrombocytopenia compared to the non-KT group. In contrast, non-hematologic toxicities, including nausea/vomiting, nephrotoxicity, hepatotoxicity, and skin rash, did not differ statistically between the two groups. Notably, only 3 patients in the KT group and 2 in the non-KT group developed >grade 2 nephrotoxicity, which was reversible after treatment, indicating mild and acceptable impacts of chemotherapy on graft kidney function; additionally, recombinant human granulocyte colony stimulating factor was used to manage high-grade hematologic toxicities, though nearly half of KT patients and one-third of non-KT patients still required chemotherapy dose reductions. These findings are valuable for clinical treatment guidance (67). Additionally, Zhang, P., et al. found that gemcitabine and cisplatin (GC) chemotherapy was somewhat effective for locally advanced disease. In seven KTRs with advanced UC, pre- and postoperative GC treatment resulted in one complete response, two partial responses, and four stable cases, with a 43% overall efficacy rate. Myelosuppression was the primary toxicity and side effect linked to the GC regimen. Other adverse reactions included reversible nephrotoxicity, gastrointestinal and cutaneous manifestations, and phlebitis. Hematologic toxicities, meanwhile, encompassed reversible leukopenia, thrombocytopenia, and anemia (84). Wang, Z.P. et al. studied 22 patients with advanced UC post KT. Eleven received surgery plus adjuvant chemotherapy (GC regimen), and the other eleven had surgery only. The group receiving adjuvant chemotherapy showed significantly better survival. KTRs with advanced UC who received surgery plus adjuvant GC chemotherapy had significantly better OS than those who only underwent surgery, with the median OS extended by 17 months. Hematologic toxicities occurred at a relatively high incidence, leading to dose reduction of chemotherapeutic agents in 45.5% of patients. Among nonhematologic toxicities, gastrointestinal reactions were the most prevalent. Grade 1 nephrotoxicity was documented in 3 patients, with no cases of higher-grade nephrotoxicity observed. Notably, serum creatinine and blood urea nitrogen levels did not show significant changes during chemotherapy. Of these eleven patients, seven had UTUC (85). These data confirm that platinum-based AC significantly improves disease control and survival in KTRs with advanced UC. While Wang, Z.P. et al. confirmed the safety of platinum-based chemotherapy for KTRs, its long-term effects on patients with ≥T2 disease are uncertain. Du et al. reported no significant impact of this chemotherapy on the prognosis of such patients. Furthermore, the effectiveness of the GC or Gemcitabine and Carboplatin (GCa) regimen in preventing distant metastasis in these recipients remains unproven (83).

Bladder instillation chemotherapy effectively reduces NMIBC recurrence. Despite lacking evidence for benefits in KTRs, immediate postoperative instillation is advised due to high recurrence risk (78). Elkentaoui H et al. conducted TURBT on NMIBC patients post KT, followed by at least one mitomycin C instillation, observing no mitomycin C-related complications. Neuzillet et al. concluded that mitomycin C is safe for KTRs and may be beneficial without added risk (86, 87). For patients with tumor recurrence after intravesical mitomycin C therapy, intravesical gemcitabine may be an option. Although typically given intravenously for metastatic bladder cancer, studies indicate that a 1000 mg intravesical dose can help prevent recurrence in high-grade NMIBC patients unresponsive to BCG therapy (88). BCG is an effective treatment for high-risk NMIBC, typically requiring at least a year of maintenance to lower recurrence and progression rates (54). However, its use in KTRs is debated due to safety concerns in immunosuppressed patients. First, the effectiveness of BCG depends on the patient’s immune response, and it may be less effective in those with weakened immunity. However, studies have shown that BCG bladder instillation chemotherapy is both safe and effective (89, 90). Second, due to the patient’s impaired immune response, BCG may spread systemically, leading to significant side effects. There have been case reports of systemic infection following bladder instillation of BCG (91). Currently, only a limited number of medical centers have experience with BCG in KTRs, and even fewer have enough patients to create guidelines. Future research should focus on optimizing BCG treatment for KTRs (92).

Neoadjuvant or adjuvant immunotherapy currently improves survival in advanced UC, especially for patients ineligible for cisplatin with few other options (93). Immune checkpoint inhibitors (ICIs), which enhance the immune response against tumors by blocking PD-1/PD-L1 pathways, have proven effective and safe in treating platinum-resistant metastatic UC. Various ICIs have demonstrated efficacy and safety comparable to chemotherapy, and pembrolizumab outperformed chemotherapy in a phase III trial (94). However, immunotherapy for UC in KTRs may still be a double-edged sword, as it may trigger T cells to attack both tumor and donor antigens. Research indicates that PD-1 can lead to kidney transplant rejection in some cases and often accelerates tumor growth (95). Some KTRs have effectively managed metastatic UC with anti-PD-1 monotherapy. In this instance, the patient showed partial tumor regression without any transplant rejection during the treatment (96). Wu CK et al. reported on a kidney transplant patient with metastatic UC treated with pembrolizumab, bevacizumab, cisplatin and gemcitabine with a continued immunosuppressants (mycophenolate mofetil and tacrolimus), leading to notable tumor reduction and stable graft function (97). Therefore, ICIs can potentially manage cancer without causing rejection. However, using ICIs in KTRs demands careful balancing of immune activation and rejection risk. As an antibody-drug conjugate (ADC), Enfortumab ventodin (EV) specifically targets the Nectin-4 protein. This protein is highly expressed in UC and has demonstrated significant efficacy in patients who have failed platinum-based chemotherapy and ICIs therapy (98). Studies have shown that EV is also well-tolerated in patients with renal impairment (99), which is particularly important for kidney transplant recipients. However, the safety and efficacy of EV in kidney transplant patients require further investigation. New treatments, like ADCs and ICIs combination therapies, are being studied and may improve patient outcomes (100). Fibroblast growth factor receptor (FGFR) inhibitors, such as erdafitinib, have shown some success in treating UC, but more experience is needed for use in post-KT patients.

When a kidney transplant recipient is diagnosed with urothelial carcinoma, it’s crucial to reduce or adjust immunosuppressive drugs to boost immune surveillance. This adjustment is necessary, especially when using ICIs, to balance tumor treatment and prevent transplant rejection (59). Close monitoring of kidney function is essential to avoid rejection, making the careful adjustment of the immunosuppressive regimen a key part of treatment.

Tacrolimus, a CNI drug, has advanced transplantation with strong short-term outcomes, but its chronic nephrotoxicity poses a challenge (101). Similarly, cyclosporine, another CNI drug, can lead to malignant tumors (102). Conversely, mTOR inhibitors may lower the risk of cancers like non-melanoma skin cancer and Kaposi’s sarcoma (103). For KTRs with newly diagnosed UC, mTOR inhibitors are typically favored over CNI drugs. Some experts recommend minimizing CNI use in immunosuppressive regimens for those at high risk of tumor development (9). Combining CNI and mTOR inhibitors allows for lower CNI doses, minimizing adverse reactions without compromising transplant outcomes; rejection rates remain similar to standard doses, while renal function improves.

Hu XP et al. assessed the safety and effectiveness of combining rapamycin (RPM) with low-dose CNI in 15 KTRs with UC. The regimen replaced mycophenolate mofetil (MMF) or azathioprine (Aza) with RPM, adjusting doses to maintain 4–6 μg/L blood levels, and reduced CNI doses to one-third after stabilization. All patients received surgical treatment and intravesical chemotherapy. Over two years, 9 patients had no tumor recurrence, 2 had two recurrences, and 4 had one. No acute rejection occurred, with hyperlipidemia and thrombocytopenia as common side effects. This approach appears to inhibit tumor growth, enhance graft function, and reduce cyclosporine nephrotoxicity, showing promising safety and efficacy (104). Combining mTOR inhibitors with tacrolimus regimens lowers the risk of UC post KT (105). However, Besarani et al. found that altering or stopping immunosuppressive therapy alongside chemotherapy offers limited benefits for patients with metastatic disease post KT (106).

In summary, adjusting immunosuppression regimens for post-KT patients with urothelial carcinoma requires careful monitoring of tumor recurrence, kidney function, and adverse reactions. Treatment should be personalized based on tumor status, incorporating surgical resection and local infusion chemotherapy to improve efficacy and quality of life. This complex process necessitates further clinical research to optimize outcomes. As shown in Table 2.